KR102579524B1 - Method for preparing porous silica particles loaded with one or more bioactive compounds adapted for pulmonary, nasal, sublingual and/or pharyngeal delivery - Google Patents

Abstract

The present invention relates to a method for preparing porous silica particles comprising one or more bioactive compounds, wherein the particles are adapted for pulmonary, nasal, sublingual and/or pharyngeal delivery of said one or more bioactive compounds, and have a particle size of 0.5 to 15 μm. It has an MMAD of and a GSD of less than 2.5. The invention also relates to pharmaceutical compositions comprising said silica particles and their use in the diagnosis, prevention and/or treatment of local and/or systemic disorders, such as pulmonary, nasal, sublingual and/or pharyngeal disorders.

Description

Method for preparing porous silica particles loaded with one or more bioactive compounds adapted for pulmonary, nasal, sublingual and/or pharyngeal delivery

The present invention relates to a method for preparing porous silica particles comprising one or more bioactive compounds, wherein the particles are adapted for pulmonary, nasal, sublingual and/or pharyngeal delivery of said one or more bioactive compounds. The invention also relates to pharmaceutical compositions comprising said silica particles and their use in the diagnosis, prevention and/or treatment of local and/or systemic disorders, such as disorders of the lung, nose, sublingual and/or pharynx.

Administration of bioactive compounds or drugs to the lungs is difficult and complex. The compound must be suitable for use in an inhalation device and formulated in a composition suitable for inhalation.

The pharmaceutical composition is preferably biocompatible, biodegradable and soluble. The particle size or diameter of the composition must be less than 6 μm to reach the lower lungs. Decomposition and dispersion of the drug upon exiting the inhalation device are important for delivery of the drug to the lungs. Particles larger than 6 μm do not enter the lower lungs, i.e. the bronchi and alveoli. Particles larger than 6 μm are suitable for drug delivery to the upper lung, throat or nose.

Compared to conventional drug delivery systems, inhaled drug delivery systems present more difficulties in understanding the various aspects of drug absorption and drug deposition patterns through the lungs due to the complexity of the respiratory system. For therapeutic efficacy, inhaled drug compositions must be more efficiently deposited in the airways and be available to produce therapeutic action locally or efficiently across the air-blood barrier to produce systemic effects. In the upper lung, the lung's epithelium contains a periciliary layer of cells with a luminal mucus layer on top of the cell layer. Any bioactive compound will have to cross the mucus layer to enter the cell layer. In the alveoli of the lower lung, the cell layer is aqueous and covered with pulmonary surfactant. Bioactive compounds must traverse the surfactant layer to reach the cell layer below. Because the mucus layer and the surfactant layer are composed of different materials, penetration through these layers requires different properties. Therefore, the site of deposition is predicted to influence the extent and rate of absorption of bioactive compounds in the lung. Compounds with water solubility above 10 μM are more readily absorbed in the upper lung, while the solubility of bioactive compounds is less important in the lower lung. However, peak systemic exposure is reduced in the lower lung when the solubility of the compound is less than 10 μM.

The deposition of inhaled particles is greatly influenced by a number of parameters, including the mass median aerodynamic diameter (MMAD), the shape and density of the particles, and the hygroscopicity of the particles. The widely accepted concept is that for efficient deposition, MMAD should be in the range of 1 to 5 μm. Smaller sized particles are more likely to be expelled, while larger particles are deposited in the upper respiratory tract. Preferably, monodisperse particles with a narrow particle size distribution are used.

Dissolution of bioactive compounds in the mucus or surfactant layer is important for therapeutic effectiveness. Compounds with low solubility and/or low dissociation constants are less effective in the lung due to lower drug exposure. In some cases, compounds of lower solubility may be used to take advantage of prolonged drug action due to longer residence time in the lung. In the case of lung disorders, the epithelium of the lung may be different, and the rate limiting step for the therapeutic effect of a bioactive compound may change from the rate of dissolution of the compound to the rate of permeation of the compound through the air-blood barrier. Deposition of the compound in different areas of the lung is also affected by the disorder. In asthma, more drug is deposited in the upper lungs compared to healthy volunteers. If less drug is deposited in the lower lungs, less drug permeates through the air-blood barrier of the alveoli, which in turn reduces the systemic effects of the drug.

Suitable pharmaceutical compositions for pulmonary delivery preferably have a controlled particle size and a sharp and controllable particle size distribution (PSD), which is advantageous for accurate pulmonary deposition. Particle size affects particle deposition in different areas of the lung. In current compositions, the particles are made from the pharmaceutical composition itself, which typically contains the bioactive compound in crystalline form together with other additives or excipients. Particle size affects the rate of dissolution of a compound from a particle or crystal. For example, pharmaceutically bioactive compounds take more time to dissolve from larger particles than from smaller particles.

The composition is preferably insensitive to humidity, as this may cause agglomeration of the composition, thereby affecting the deposition pattern of the particles.

Pharmaceutical compositions suitable for pulmonary delivery of drugs or bioactive compounds are dry powder compositions. These compositions are often limited to the use of crystalline drugs because oily or amorphous compounds are very difficult to formulate into dry powders that can be used for constant and unchanging administration.

Porous particles have been developed to improve the delivery of bioactive compounds to the lungs, such as improved control over particle size, improved loading of drugs in particle compositions, improved controlled release of bioactive compounds, etc. Delivery of bioactive compounds can be topical, systemic, and immediate or extended release.

US6,740,310 discloses dry powder compositions for cardiopulmonary delivery of bioactive compounds comprising spray dried porous or non-porous particles, wherein 55% of the particles have an aerodynamic diameter (MMAD) of less than 4.7 μm. , the mass density is less than 0.1 g/cm3.

US6,254,854 discloses dry compositions comprising biodegradable particles for delivery of bioactive compounds in the cardiopulmonary system, wherein the particles are made of polyester copolymers, have a mass median diameter (MMD) of 5 to 30 μm, and have a median aerodynamic The diameter (MMAD) is 1 to 5 μm and the mass density is less than 0.4 g/cm3.

The parameters of the particles are controlled by the manufacturing and separation method. Important parameters are mass median diameter (MMD) and mass median aerodynamic diameter (MMAD). The particles produced in the manufacturing process often have a wide range of diameters, where the distribution of the ranges follows a Gaussian curve (see Figure 6). The parameter used to define the distribution of MMAD is the geometric standard deviation (D _84.1 /D _15.9 ) ^1/2 (GSD). Figure 5 shows the relationship between aerodynamic diameter (MMAD) and lung deposition. Particles 4-5 μm in size are mainly deposited in the bronchi, while smaller particles (about <4 μm) remain in the airstream and are transported to the peripheral airways and alveolar regions of the lower lungs. Other parameters used to define particles are mass density and fine particle fraction (FPF). FPF is the proportion of particles with a diameter of less than 5 μm. Other particle parameters that are important are the shape of the particle, the surface area, and the pore volume of the particle.

The selection of particles within the desired range is generally carried out by separating the particles loaded with the bioactive compound, for example using a filter to obtain 55% of the particles within the desired range, such as having a diameter of less than 4.7 μm. .

Tartula O, et al., J. Drug Targeting, 2017, 19(10, p 900-914) disclose a lung cancer treatment strategy using nanotechnology, in which silica particles are prepared using a surfactant-template method. The particles are manufactured with a uniform size of 160 nm +/- 75. After loading, the average size is 200 nm +/- 100. The surface of the particles is first conjugated with pyridylthiol after the particles are loaded with DOX or CIS. Then, the pyridylthiol conjugate is replaced by iRNA and LHRH conjugate.This preparation method is specific for the bioactive compound used, is time-consuming and expensive.

WO2003/011251 discloses loaded particles prepared by etching, filtration or grinding to obtain microparticles of porous silicon particles of monodisperse size and shape. It is mentioned that the particles can be loaded with biologically active substances before or after the grinding process. No examples of loaded particles with a narrow size distribution are disclosed. Unfortunately, after publication of this application, it has become known that silicon can cause serious adverse effects in the lungs.

US2015224077 discloses a method for producing particles using nebulization. Although it is mentioned that porous particles can be used, examples of the production of loaded porous particles are not disclosed.

GB2355711 discloses a method of making particles, wherein the particles are sized during manufacture of the particles. Sizing is preferably carried out by sieving, since the use of air classifiers is expensive. However, it is mentioned that both methods of sizing cannot be used to obtain highly purified porous silica particles.

WO2008150537 discloses a process for preparing porous silica particles for use in chromatography. Particles may be sized prior to use. No loading of the particles is mentioned, nor is any separation of the sizes of the particles mentioned before loading with the bioactive compounds.

Inhalation devices can be metered dose inhalers (MDI), dry powder inhalers (DPI) and mist inhalers (SMI). DPI is the most widely used, and it can be divided into low, medium, and high resistance DPI. Pharmaceutical compositions used in these devices often include additives such as propellants, surfactants, antioxidants, humidity regulators, etc.

The efficiency of these devices is affected by two main forces: 1) inspiration air flow (IAF) (depending on the flow generated by the patient), and 2) turbulence generated by the device. The balance between these two forces is important for optimal performance of the device. If the IAF is too high, most of the drug is lost in the upper lungs, i.e. the throat and trachea. If the IAF is too low, more drug is delivered to the lower lungs, i.e. the bronchi and alveoli, but the breakdown and dispersion of the drug is low. Most used are DPIs with medium resistance, since these devices are less dependent on IAF for degradation and dispersion of the composition in the lung.

Other technologies for inhalation compositions have been developed. Compositions of fixed-dose drug combinations must ensure powder homogeneity and delivery of uniform doses to the patient, especially when the proportions of each drug present in the formulation are significantly different. In an attempt to reach these requirements and achieve co-deposition of drugs in the lung, particle engineering has been used instead of simple blending of micronized drugs with coarse carrier particles. Pearl Therapeutics (California, USA) used a method to prepare triple fixed-dose combination formulations. First, an emulsion of DSPC (1.2-distearoyl-sn-glycero-3-phosphocholine) and anhydrous calcium chloride is spray dried to form porous microparticles. The porous particles and micronized glycopyrrolate, formoterol fumarate, and mometasone furoate were then co-suspended in 1,1.1.2-tetrafluorothane (HFA) propellant. The drug microparticles attach irreversibly to the porous particle surface, forming a stable suspension in which the delivered dose for each drug is equivalent.

Another attempt to prepare homogeneous compositions of triple fixed-dose combinations was conducted by Parikh D, Burns J, Hipkiss D, Usmani O, et al. Improved localized lung delivery using smart combination respiratory medicines. European Respiratory Disease. Reported by 2012;8(1):40-5. The solution atomization and crystallization method (SAXTM) involves the formation of drug-concentrated droplets followed by ultrasonic sono-crysta treatment (to create cavitation bubbles for rapid nucleation and crystallization). It is a method that entails. This method produces powder formulations with appropriate dose-delivery homogeneity and aerodynamic properties.

Different micronization methods have been used. A disadvantage of these micronized powders is that the dissolution rate of the drug is dependent on the particle size of the powder and characteristics of the drug such as solubility. Accordingly, delivery of bioactive compounds still relies on the turbulence generated by the IAF and the delivery device.

The shape of the particles is important for the flow dynamics of the particles and the dissolution and deposition of bioactive compounds contained in the particles. It is difficult to produce spherical or pseudo-spherical, cylindrical particles of micromillimeter size, i.e. particles with a diameter greater than 2 μm, or between 1 and 50 μm.

It is an object of the present invention to overcome, at least in part, the above problems and to provide an improved process for the preparation of porous silica particles loaded with or comprising one or more bioactive compounds, wherein the particles are sublingually loaded with said one or more bioactive compounds. , adapted for pulmonary, nasal and/or pharyngeal delivery.

This object is achieved by a process for producing loaded porous silica particles comprising at least one bioactive compound, comprising or consisting of the following steps:

- providing silica particles,

- separating the particles to obtain particles with an MMAD of 0.5 to 15 μm and a GSD of less than 2.5,

- loading the obtained particles with one or more bioactive compounds, and

- optionally loading the particles with additional bioactive compounds.

In one aspect, the particles have an MMAD of between 0.5 and 5 μm and a GSD of less than 2.5, or an MMAD of between 5 and 15 μm and a GSD of less than 2.5.

In one aspect, the particles have an MMAD of between 0.5 and 3.5 μm and a GSD of less than 1.5.

In another aspect, the particles have an MMAD of 6 to 12 μm, or 8 to 12 μm and a GSD of less than 2.

The method allows for separation of particles prior to attachment or loading of bioactive compounds. Alternatively, the bioactive compound can be prepared as nanocrystals and adsorbed onto silica particles. The method improves the yield and efficiency of the manufacturing method. This reduces manufacturing costs compared to methods where separation is performed after attachment of the particles to the bioactive compound. Higher amounts of bioactive compounds may be present in the final composition.

Another advantage is that the method can be used independent of the morphology of the compound. Crystalline, oily and amorphous compounds can be attached to or loaded into particles and can be used in the methods of the present invention. This also allows the production of particles that can be delivered topically or systemically, improving the flexibility of treatment of any disease. This improves the flexibility of treatment of airway disorders such as lung, nose and pharyngeal disorders. Dissolution of the compound from the particle is independent of the morphology of the compound and independent of the site of delivery of the compound. Dissolution is improved in the lower as well as the upper lung because the compound is dissolved from particles in both the surfactant layer as well as the luminal mucus layer.

The method allows control of parameters of the particles that are important for the delivery of bioactive compounds, such as MMAD and GSD. As explained above, these parameters are different for delivery of particles (and bioactive compounds) to the lower lungs compared to delivery to the upper lungs or throat (including the sublingual cavity under the tongue) or nasal cavity. . The method allows selection of a narrow size distribution of particles with a GSD of less than 4, or 2.5, or 1.5, prior to loading or attachment of bioactive compounds to the particles. This improves the monodispersity of particle size, allowing control of the site of particle deposition in the lung. Additionally, the homogeneity of the composition containing the particles can be improved.

Additionally, more than one bioactive compound can be loaded into and/or attached to the particle without any substantial loss of material. This further reduces particle manufacturing costs. The method is relatively simple compared to methods known in the art.

In one aspect, the invention relates to a process for preparing porous silica particles comprising one or more bioactive compounds comprising or consisting of the following steps:

- providing silica particles,

- separating the particles to obtain particles with an MMAD of 0.5 to 15 μm and a GSD of less than 2.5.

Accordingly, the method can be used for the delivery of empty porous particles. These particles may be useful in the treatment of diseases such as diabetes and obesity, and may reduce blood cholesterol, especially LDL.

The outer surface of the amorphous silica can be tailored to minimize agglomeration of particles. Reduced agglomeration of particles reduces dependence on the turbulence and inspiratory air flow (IAF) generated by the inhalation device. This improves the balance between the two forces discussed above, improving the efficiency of delivery of bioactive compounds to the lower lung without loss of bioactive compounds in the upper lung. Flocculation may depend on the bioactive compounds loaded or attached to the particles. Aggregation can be prevented by the use of certain bioactive compounds.

In another aspect, the method includes or consists of the additional step of surface modification of the particles prior to loading or prior to separation. In one aspect, surface modification is performed prior to separation. In a further aspect, surface modification is performed prior to loading. Surface modifications, such as chemical surface modifications, such as etching, lead to an altered surface of the silica particles. This can be useful in preventing particles from agglomerating. This is particularly useful when the particles have a size of 10 or 6 μm or less. Surface modification of the particles prior to loading does not appear to affect the rate of dissolution of bioactive compounds from the particles.

In a further aspect, the method comprises or consists of the additional step of surface modification of the particles by coating after production or after loading. In one aspect, coating is performed post-fabrication. In a further aspect, coating is performed after loading. Coatings can be used to attach bioactive compounds to the surface of the particles. Coatings can be used to provide an electrical charge to the surface of the particles, thereby preventing their agglomeration. This is particularly useful when the particles have a size of 10 or 6 μm or less. In one aspect, the particles are coated with a functionalizing agent. In one aspect, the particles are coated with a surfactant. In another aspect, the particles are coated with an amino acid selected from the group comprising or consisting of L-lysine, L-alanine, glycine, leucine, and L-tyrosine. The coating may be performed to block the pores of the particles, or the coating may be performed without blocking the pores of the particles.

In another aspect, the method comprises or consists of the additional step of surface modification of the particles prior to separation or prior to loading, wherein the surface modification includes chemical surface modifications, such as etching and coating (e.g., non-blocking of pore coatings). )) am.

Particles may be prepared by any method known in the art. In one aspect, particles are prepared by reacting tetraethyl orthosilicate with a template made of micellar structures. Additionally, tetraethyl orthosilicate can be used with additional polymers as templates. In another aspect, the particles are prepared by a sol-gel method, such as the Stoeber method, or by a spray drying method. In a further aspect, the silica particles are prepared by a sol-gel process comprising the condensation reaction of a silica precursor solution with an immiscible organic solution, oil, or liquid polymer, wherein the droplets are formed at a pH of It is formed by gelation of silica by changes in and/or evaporation of the aqueous phase. The sol-gel method has advantages over other methods in that it is less cumbersome, less expensive, and geared toward large-scale production of silica particles under Good Manufacturing Practice (GMP).

In one aspect, the silica particles are nano-porous and/or meso-porous silica particles. In another aspect, the particles are nanoporous silica particles. In one aspect, the particles are mesoporous silica particles. In a further aspect, the silica particles are spherical, pseudo-spherical, cylindrical, gyroidal, rod-shaped, fiber-shaped, core-shell shaped particles. In a further aspect, the silica particles are spherical or cylindrical. This can improve the flow dynamics of particles. The shape of the particles can be controlled by the manufacturing method. This can be important for deposition and dissolution of bioactive compounds.

In one aspect, the silica particles are biodegradable. In one aspect, the silica particles are soluble. In one aspect, the particles are biodegradable and soluble. In a further aspect, the silica is synthetic amorphous silica. For some applications, it is advantageous if silica is biocompatible, soluble and biodegradable. This may reduce the possible toxic effects of the particles on the lungs, nose and throat, especially the heart and lungs.

In another aspect, the silica particles have a pore size between 1 and 100 nm. In yet another aspect, the silica particles have a pore volume of 0.1 to 3 cm3/g. In a further aspect, the silica particles have a surface area of 40 to 1200 m2/g. Measurements were performed by nitrogen adsorption isotherms and calculated using the Brunauer-Emmett-Teller (BET) model to calculate pore volume and pore size. In another aspect, the silica particles may have a pore size of 1 to 100 nm, a pore volume of 0.1 to 3 cm3/g, and a surface area of 40 to 500 m2/g.

Particles may be separated by any method known in the art. In one aspect, the particles are separated using an air classifier, or cyclonic separation, or clarification, or sedimentation, and/or sieving using one or more sieves. In a further aspect, particles are separated using an air classifier.

Particles may be loaded by any method known in the art. In one aspect, the particles are loaded using solvent evaporation, impregnation, spray-drying, melting, supercritical CO ₂ loading, or freeze-drying. In a further aspect, particles are loaded using solvent evaporation. The term “loading” means that a bioactive compound can be loaded into and/or onto, or otherwise attach to, a particle. The advantage of loading a compound into porous silica particles is that the dissolution rate of the compound is affected by the pore structure, such as the pore volume, rather than the size of the silica particle. This leads to the dissolution kinetics of the compound being independent of particle size. Particle size is a key parameter determining particle deposition in the lung. Accordingly, the dissolution kinetics of a compound can be tuned and independent of the location of the particle in the lung. By using silica porous particles, dissolution of the compound from the particle is independent of the morphology of the compound and independent of the site of delivery. With the method of the invention, compositions can be obtained, wherein the delivery of the bioactive compound is less dependent or not dependent on the morphology of the compound, or is less dependent or not dependent on the turbulence caused by the delivery device, compared to known compositions. , is less or less dependent on the inspiratory air flow generated by the patient.

In one aspect, silica particles are prepared using a sol-gel method, the silica particles are separated using an air classifier, and the particles are loaded using solvent evaporation.

In a further aspect, the particles have a fine particle fraction of at least 90%, or 99%, or 99.8%.

For delivery of bioactive compounds in the cardiopulmonary system, the particles have an MMAD of 6 μm, or 3 μm, or 0.5 to 5 μm, or 1 to 3.5 μm, and a GSD of 2.5, or 2.2, or 2.0, or 1.8, or 1.5. It is less than.

For delivery of bioactive compounds in the sublingual, nasal and/or pharyngeal cavities, the particles have an MMAD of at least 5, or 10 μm, or 5 to 15 μm, or 6 to 12 μm, or 8 to 12 μm, or 7.5 to 7.5 μm. 11.5 μm, and the GSD is less than 4, or 2.5, or 2, or 1.5. In another aspect, GSD is 1 to 2. The advantage of the method of the invention is that “monodisperse” particles with a narrow range distribution (i.e. low MMAD and narrow GSD) can be obtained. This means that the site of particle deposition in the lung can be adjusted with improved accuracy compared to prior art particles. For example, more particles and therefore more bioactive compounds can be delivered to the heart and lungs. This also improves the homogeneity of the particle-containing composition.

In yet another embodiment, the particles have a mass density of less than 0.4 g/cm3, or between 0.15 and 0.35 g/cm3. In still a further aspect, the particles have a fine particle fraction (FPF) of at least 75%, 80%, 85%, 90%, 95%, 98%, 99% or 99.9%, or 100%. In one aspect, the FPF is 98 to 100%, or 99 to 100%, or 99.5 to 100%. MMD or MMAD can be variable depending on the site of delivery of the bioactive compound. Accordingly, for lower pulmonary delivery the MMAD may be less than 3 or 6 μm, while for nasal delivery the MMAD may be greater than 10 μm. The GSD may be the same for both lower pulmonary and nasal delivery. Alternatively, a dosage having more than one selected MMAD, such as 50% of the particles having an MMAD of 1 to 3 μm and a GSD of 1 to 1.5, and 50% of the particles having an MMAD of 10 μm or greater and a GSD of 1 Dosages ranging from 2 to 2 can be used.

The invention also provides a plurality of particles loaded from 0.1 to 80%, or from 5 to 50% of the total weight of the loaded particles, having one or more bioactive compounds, and optionally other pharmaceutical excipients, diluents or additives, optionally coated with a functionalizing agent. A pharmaceutical composition adapted for pulmonary delivery of a bioactive compound comprising or consisting of porous silica particles, wherein the particles have an MMAD of 0.5 to 5 μm and a GSD of less than 2.5. In one aspect, the particles have an MMAD of between 0.5 and 3.5 μm and a GSD of less than 1.5. In another aspect, the particles have been prepared according to the manufacturing method defined above.

The invention also includes a plurality of porous silica particles having one or more bioactive compounds, and optionally other pharmaceutical excipients, diluents or additives, and loaded from 0.1 to 80%, or from 5 to 50% of the total weight of the loaded particles, or A pharmaceutical composition adapted for sublingual, nasal and/or pharyngeal delivery of a bioactive compound comprising the particles, wherein the particles have an MMAD of 5 to 15 μm and a GSD of less than 2.5. In one aspect, the particles have an MMAD of 8 to 12 μm and a GSD of less than 2. In another aspect, the particles have been prepared according to the manufacturing method defined above.

Pharmaceutical compositions can be used for topical and/or systemic delivery of one or more bioactive compounds.

Pharmaceutical compositions can be used for immediate and/or extended release of one or more bioactive compounds. When more than one bioactive compound is present in or on the particles of the composition, one bioactive agent may be delivered locally while the second bioactive agent may have a systemic effect. Additionally, different bioactive compounds may be released from the particles at different rates.

In yet another aspect, the bioactive compound is a crystalline, amorphous or oily compound. In one aspect, the bioactive compound is an amorphous compound. The compositions of the present invention are capable of delivering a constant/uniform drug dose, which is independent of the solubility of the bioactive compound. That is, the dissolution rate is not affected by the morphology of the bioactive compound. When the therapeutic use of a compound no longer depends on its morphological form or solubility, more bioactive compounds can be developed, which improves flexibility in the development of new drugs and in the treatment and diagnosis of patients. Even in combination therapy, homogeneity of dosage is ensured and uniform doses of more than one bioactive compound can be administered to the patient.

In another aspect, the bioactive compound has a water solubility at 25° C. of Ph.Eur 9 ^th Ed. Depending on the level, it is more than 10 mg/ml. An example of a bioactive compound would be metoclopramide, which has a solubility in buffer of 10 mg/ml and a solubility in water >6 mg/ml at pH 6.8.

Also in another aspect, the bioactive compound has a water solubility at 25° C. of Ph.Eur 9 ^th Ed. Depending on the range, it is 1 to 10 mg/ml. In one aspect, the bioactive compound has a water solubility at 25° C. of Ph.Eur 9 ^th Ed. Accordingly, it is less than 1 mg/ml. Porous particles can improve the dissolution kinetics of bioactive compounds with poor water solubility, that is, bioactive compounds with a water solubility of less than 10 mg/ml at 25°C. Examples of bioactive compounds could be clofazimine (which has a solubility of 0.225 mg/l) or OSU-03012 (which is water insoluble) or folic acid (which has a solubility of 1.6 mg/l).

By using particles, larger amounts of bioactive compounds can be delivered to the delivery site compared to known compositions. This means that the frequency of administration can be reduced, thereby reducing the effectiveness and efficacy of treatment as well as the costs for health care. Silica particles are compatible with most additives and can be blended with other additives without any problems. Additionally, fewer additives are required in the compositions of the present invention, which reduces the cost of manufacturing the compositions. Additionally, silica, especially amorphous silica, is less sensitive to humidity than the dry crystalline powder compositions currently used in inhalers. This reduces the risk of agglomeration of particles and consequently reduces the dependence of the device on turbulence and IAF by using particles prepared according to the method of the invention. The loading capacity of the particles is increased compared to prior art particles. Additionally, loading of bioactive compounds into (nano)porous silica provides compounds in a stable amorphous state, which improves controlled release and dissolution kinetics. The particles have improved homogeneity even when the particles contain more than one bioactive compound.

Improved efficacy of deposition of the bioactive compound in the lung allows for more precise lung delivery, improving the therapeutic effect of the compound both locally and systemically. Exposure of bioactive compounds to the lungs, pharynx, or nose is increased. Additionally, silica particles allow for higher dose delivery to specific areas.

In another aspect, the bioactive compound is selected from the group comprising or consisting of: anti-allergic agent, bronchodilator, pulmonary lung surfactant, analgesic agent, antibiotic, anti-infective agent, leukotriene inhibitor or antagonist, Antihistamines, anti-inflammatory agents, antineoplastic agents, anticancer agents, anticholinergics, anesthetics, antitubercular agents, cardiovascular agents, enzymes, steroids, genetic material, viral vectors, antisense agents, proteins, peptides and combinations thereof. In one aspect, the bioactive compound is a protein or peptide, such as a tripeptide, growth factor, or oligonucleotide.

In a further aspect, the bioactive compound is selected from the group comprising or consisting of: gefitinib, dasatinib, imatinib, bosutinib, diclofenac (sodium), felodipine, indapamide, itraconazole, and quefitinib. Tiapine.

In one aspect, the bioactive compound is selected from the group comprising or consisting of: clofazimine (NC009), OSU-03021 (N023), and folic acid (NC026).

The invention further relates to a delivery device adapted for pulmonary, nasal, sublingual and/or pharyngeal delivery of one or more pharmaceutical bioactive compounds comprising or consisting of a pharmaceutical composition as defined above, optionally mixed with a propellant. In one aspect, it is selected from the group consisting of or consisting of a hydrocarbon, fluorocarbon, hydrogen-containing fluorocarbon, or mixtures thereof that have a vapor pressure sufficient to efficiently form an aerosol upon activation of the metered dose inhaler. In one aspect, the pharmaceutical composition does not include or consist of a propellant. The compositions of the present invention reduce the need for co-development of inhalation devices. The delivery device may be a metered dose inhaler (MDI), dry powder inhaler (DPI), or mist inhaler (SMI). The delivery device may be a dry powder inhaler (DPI), especially a DPI with media resistance. Additionally, these delivery devices reduce the dependence of delivery of the compound on turbulence and IAF of the device for degradation and dispersion of the compound in the lung.

In metered dose inhalers, the pharmaceutical composition is in liquid form as a solution or suspension. It can be difficult to prevent dissolution of bioactive compounds from or leakage of compounds from particles. Typically, the solvent or surfactant is selected to keep the suspension of drug particles stable. Typically, the compounds have low solubility in the solvents used. Stable compound suspensions can be prepared by loading the compound into silica particles. Silica particles are well dispersed in different solvents and can be further modified, for example by coating the particles, to prevent dissolution or leakage of the drug into the solvent before delivery to the target site or lung. The advantage of loading with silica is that a wide range of compounds can be formulated as drug suspensions. Additionally, while silica particles have high drug loading capacity, most formulations have limited compound/drug concentration per particle. Additionally, compounds of any morphology can be loaded onto the particles and used in the device.

The invention further relates to the diagnostic, prophylactic and/or therapeutic use of the pharmaceutical compositions as defined above. In one aspect, the pharmaceutical composition as defined above is used to treat pulmonary diseases selected from the group comprising or consisting of infections, inflammation, COPD, asthma, cancer, tuberculosis, severe acute respiratory syndrome, respiratory syncytial virus, influenza, smallpox and drug-resistant respiratory infections. , can be used in the diagnosis, prevention and/or treatment of local and/or systemic disorders of the nose, sublingual space or pharynx. Diagnosis, prevention of local and/or systemic disorders of the lung selected from the group including or consisting of infection, inflammation, COPD, asthma, cancer, tuberculosis, severe acute respiratory syndrome, respiratory syncytial virus, influenza, smallpox and drug-resistant respiratory infections. and/or an aspect related to treatment. One aspect related to the diagnosis, prevention and/or treatment of a local and/or systemic disorder of the lung, wherein the disorder is cancer and the compound is selected from gefitinib, dasatinib, imatinib, bosutinib.

The present invention provides for pulmonary, nasal, sublingual and/or pharyngeal administration of pharmaceutical compositions comprising or consisting of a plurality of porous particles loaded with one or more bioactive compounds, optionally in admixture with a propellant and optionally with other pharmaceutical excipients, diluents or additives. Relating to a coordinated dry powder device,

Here the particles were prepared by:

- providing porous particles, preferably by sol-gel method or spray drying method,

wherein the particles have a pore size of 1 to 100 nm, a pore volume of 0.1 to 3 cm3/g and a surface area of 40 to 1200 m2/g,

Particles are pseudo-spherical or cylindrical;

- Before loading, the particles are separated, preferably using an air classifier, or cyclonic separation, or clarification, or sedimentation and/or sieving, more preferably using an air classifier.

Obtaining particles with an MMAD of 0.5 to 15 μm, a GSD of less than 2.5 and an FPF of at least 99.0%,

- loading the particles with one or more bioactive compounds, preferably by solvent evaporation, impregnation, spray-drying, melting, supercritical CO ₂ loading or freeze-drying, more preferably by solvent evaporation,

wherein the porous silica particles are loaded with at least 5% w/w of one or more bioactive compounds;

- optionally modifying the surface of the particles, preferably without clogging the pores, preferably by etching and/or coating,

- optionally loading the particles with additional bioactive compounds,

Here, the concentration of porous silica particles in the pharmaceutical composition is 5% w/w or more based on the total weight of the pharmaceutical composition.

Bioactive compounds include gefitinib, dasatinib, imatinib, bosutinib, diclofenac (sodium), felodipine, indapamide, itraconazole, quetiapine, clofazimine (NC009) and OSU-03021 (NC023) and folic acid. (NC026).

Any interval of a feature may be replaced by another interval of the same feature mentioned herein.

The present invention will be explained in more detail with reference to the accompanying drawings and description of different aspects of the invention.
Figure 1 shows a flow diagram of the preparation, separation and loading method of porous silica particles.
Figure 2 shows particle size distribution determination by the Marple Cascade Impactor of NLAB-silica before and after air classification.
Figure 3 shows TGA results of NLAB silica encapsulated with NC009 and NC023 as bioactive compounds.
Figure 4 shows particle size distribution determination by Marple cascade bombardment of naked NLAB silica and NLAB silica encapsulated bioactive compounds.
Figure 5 shows the International Commission on Radiation Protection Model showing the relationship between aerodynamic diameter and lung deposition (Koebrich R, Ann Occup Hyg, 1994, 38, 588-599)
Figure 6 illustrates the parameters used for particle diameter distribution.
Figure 7 shows the dissolution kinetics of NLAB-silica particles in SLF at 37°C.
Figure 8 shows the dissolution kinetics of NLAB-silica particles with different pore structures in SLF at 37°C.

What is it and how to measure it?

As used herein, “bioactive compound” means a pharmaceutically (bio)active compound that has a preventive, prophylactic or therapeutic effect in/on the mammalian body, such as humans. Bioactive compounds may be biologically active compounds such as proteins, peptides, antibodies, etc.

As used herein, the term “disease” is intended to include a disorder, condition or any equivalent thereof.

The term “loading” means that a bioactive compound can be loaded into and/or on a particle or otherwise attached to a particle.

The term “extended release” means any release of the bioactive compound that is not immediate, i.e. at least 80% of the compound is not released within 30 minutes.

As used herein, the term “patient” refers to a mammal, eg, a human.

As used herein, the term “substantially” or “about” means a deviation of a value around the stated number, for example substantially or about 5 may be a value between 4 and 6.

As used herein, the term “coating” means a covering of a surface, which may or may not include blocking pores.

As used herein, the term “surface modification” means modification of a surface, change in its physical and/or chemical properties.

In the context of this specification, the term “treatment” also includes “prophylaxis” unless specifically indicated to the contrary. The terms “therapeutic” and “therapeutically” are to be interpreted appropriately. The term “therapy” within the context of the invention further includes administering an effective amount of a compound of the invention to alleviate a pre-existing disease state, acute or chronic, or relapsing. This definition also includes continued therapy for chronic disorders and prophylactic therapy for prevention of recurrent conditions.

As used herein, the term “optionally” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances in which the event or circumstance occurs and instances in which it does not.

As used herein, the term “compound” refers to natural or synthetic compounds as well as any natural or synthetic biological compounds, such as peptides, growth factors, oligonucleotides, etc.

NC009 refers to clofazimine, N,5-bis(4-chlorophenyl)-3-propan-2-yliminophenazin-2-amine, CAS 2030-63-9, and N023 refers to OSU-03021 2 -Amino-N-(4-(5-(phenanthren-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)acetamide, CAS 742112-33-0 NC026 is folic acid, N-(4-{[(2-amino-4-oxo-1,4-dihydropteridin-6-yl)methyl]amino}benzoyl)-L-glutamic acid, CAS 59 It means -30-3.

Mercury (Hg) intrusion is the standard method for measuring porosity. In this method, mercury is forced into a pore under applied pressure. However, there is a lower pore size limit of about 3.2 nm, below which mercury cannot penetrate. For porous materials with pore sizes in the mesoscale range of 1 to 50 nm, nitrogen (N ₂ ) sorption is commonly used to estimate pore size and pore volume. Nitrogen sorption techniques measure the available surface area of porous materials. Empirical models are used to calculate pore volume and pore size. The Brunauer-Emmett-Teller (BET) and Barrett, Joyner and Halenda (BJH) models are used to calculate the porosity for the pores of silica particles.

Scanning electron microscopy (SEM) can be used to provide images of porous particles. The diameter of the particles can be determined using SEM.

The porous particles may contain silica species and organic templates, such as cationic surfactants such as alkyltrimethylammonium templates (variable carbon chain length) and counterions such as cetyltrimethylammonium chloride (CTA+Cl- or CTAC) or cetyltrimethylammonium bromide ( CTA+Br- or CTAB) or nonionic species such as diblock and triblock polymer species such as copolymers of polyethylene oxide and polypropylene oxide, such as Pluronic 123 surfactant. It can be. The formation of mesoporous silica particles occurs following hydrolysis and condensation of silica precursors, which may include alkyl silicates such as tetraethylorthosilicate TEOS or tetramethylorthosilicate TMOS in solution or sodium silicate solution. Mesoporous silica particle size can be controlled by adding suitable additives, such as inorganic bases, alcohols including methanol, ethanol, propanol, and organic solvents such as acetone, which affect the hydrolysis and condensation of the silica species. there is. The pore size can be influenced by hydrothermal treatment of the reaction mixture, such as heating to or even above 100° C., and also by the addition of swelling agents in the form of organic oils and liquids that expand the surfactant micellar template. After condensation of the silica matrix, the templating surfactant can be removed by calcination, typically at temperatures below 500°C to 650°C for several hours, which burns the organic template and leads to a silica porous matrix. The template can alternatively be removed by extraction and washing with a suitable solvent, such as an organic solvent or an acidic or basic solution.

Porous silica particles are silica precursor solutions, such as sodium silicate or emulsions, of silica nanoparticles, in which droplets are formed by gelation of the silica through changes in pH and/or evaporation of the aqueous phase, for example after stirring or spraying the solution. It can be prepared by a sol-gel process involving the condensation reaction of an aqueous suspension with an immiscible organic solution, oil or liquid polymer. Here, the porosity of the particles is formed by jamming of silica nanoparticles during evaporation or by exclusion due to the presence of an immiscible secondary phase. The particles can be further processed by heating to induce condensation of the silica matrix and washing to remove the immiscible secondary phase. Additionally, the particles can be treated by calcination to strengthen the silica matrix.

The porous particles are prepared as porous glasses by phase separation in borosilicate glass (eg SiO ₂ -B ₂ O ₃ -Na ₂ O) followed by liquid extraction of one of the formed phases via the sol-gel method; Alternatively, it can be produced simply by sintering glass powder. During heat treatment, typically at 500°C to 760°C, an interpenetrating structure is created, which derives from radial decomposition of the sodium-rich borate phase and the silica phase.

Porous particles can be produced using fumed methods. In this method, fumed silica is prepared by combustion of silicon tetrachloride in an oxygen-hydrogen flame, producing microdroplets of fused silica that fuse into three-dimensional secondary particles of amorphous silica particles and then agglomerate into tertiary particles. do. The obtained powder has a very low bulk density and high surface area.

Figure 1 shows a flow diagram of the method of the invention for the preparation of porous silica particles loaded with or comprising one or more bioactive compounds. The term “loading” means that a bioactive compound can be loaded into and/or on a particle or otherwise attached to a particle. The resulting particles are adapted for pulmonary, nasal, sublingual and/or pharyngeal delivery of the one or more bioactive compounds. The method includes or consists of the steps outlined below.

In the first step, silica particles are provided. The present invention is not limited to any particular manufacturing method. An example of a manufacturing method is disclosed in WO2009/101110. Other methods are mentioned above.

In the second step, the particles are separated to obtain particles with an MMAD of 0.5 to 15 μm and a GSD of less than 2.5.

Separation can be performed using an air classifier. Air classifiers are industrial machines that separate particles by a combination of size, shape and density. It operates by feeding raw particles to be classified into a chamber containing a column of rising air. Inside the separation chamber, air resistance to the particles provides an upward force, which cancels out the force of gravity and lifts the particles to be sorted into the air. Due to the dependence of air resistance on particle size and shape, particles in a column of moving air are sorted vertically and can be separated in this way. Examples of suitable air classifiers may be Stage Non Viable Cascade Impactor, Marple Miller Impactor or Multi-stage Liquid Impinger.

Separation may also be performed by air classifier, or cyclonic separation, or clarification, or sedimentation and/or sieving using one or more sieves.

In the third step, the particles obtained in two steps are loaded with or attached to one or more bioactive compounds. More than one bioactive compound may also be loaded. Additionally, particles can be functionalized by the use of biomarkers, such as radioactive agents, contrast or fluorophores, which can be attached to or loaded onto/into the particles.

Particles can be loaded using different techniques, such as solvent evaporation, impregnation, spray-drying, melting, supercritical CO ₂ loading or freeze-drying. Solvent evaporation involves combining a concentrated solution of the bioactive compound with silica particles, followed by removing the solvent and/or drying the sample before further processing.

The loading of porous silica particles may be greater than about 5% w/w, or about 15%, 20%, 25%, 30%, 40%, 50%, 75%, 80%, 85%, 90%.

Optionally, a second or subsequent loading step is performed. This can be done in order to increase the loading of one or more bioactive compounds in step 3, or it can be done in order to load the particles obtained in step 3 with a second or subsequent bioactive compound. Different bioactive compounds can be mixed with the porous particles and/or different bioactive compounds can be loaded into the porous particles and/or loaded onto the porous particles. The invention is not limited to any combination thereof.

The method may include or consist of the additional step of surface modification of the particles before loading or prior to separation. Surface modification is preferably carried out before loading. Surface modification may be a chemical modification, such as etching. Etching can be performed by boiling silica particles in a base and then in acid to form -S-OH bonds on the outer surface of the particles. Examples of suitable bases may be KOH, aqueous n-propanol solution, NaBH ₄ , or HF, or NaOH or N ₂ CO ₃ and ammonia solution. Examples of suitable acids may be HCl and H ₂ SO ₄ .

The method may include or consist of the additional step of coating the particles after loading or after production. Coating is preferably carried out before loading. Preferably, the pores are not clogged by the coating. At least some of the entire particles may be coated. The coating may be a taste-masking coating or a mucoadhesive coating. Coatings can also be used to improve hydrophilicity or lipophilicity. Coatings can even be used to charge particles on a surface.

Suitable coating agents include functional groups selected from the group consisting of or consisting of amino acids, surfactants, polymers, lipids, cellulose or derivatives thereof, saccharides, stearates such as magnesium stearate, peptides, proteins and nanoparticles (which may be porous). It could be a hot topic. Examples of amino acids may be L-lysine, L-alanine, glycine, leucine, and L-tyrosine.

The silica particles may be nanoporous or mesoporous or mixtures thereof. The silica particles may have a pore size of 1 to 100 nm, or 1 to 80 nm, or 2 to 50 nm, or 2 to 25 nm, or 5 to 15 nm, or substantially 12 nm.

The silica particles have a pore volume of 0.1 to 3 cm3/g, or 0.2 to 2 cm3/g, or 0.5 to 1.5 cm3/g, or 0.7 to 1.2 cm3/g, or 0.5 to 1.0 cm3/g, substantially 8.5 cm3/g. It can be g.

The silica particles may have a surface area of 40 to 1200 m2/g, or 60 to 1100 m2/g, or 100 to 1000 m2/g, or 50 to 800 m2/g, or 50 to 600 m2/g. As used herein, particles may have any combination of the intervals mentioned above. For example, silica particles can have a pore size of 2 to 100 nm, a pore volume of 0.1 to 3 cm3/g, and a surface area of 100 to 1000 m2/g. The silica particles may have a pore size of 2 to 50 nm, a pore volume of 0.5 to 1.5 cm3/g, and a surface area of 50 to 800 m2/g.

Silica particles can have different shapes. The shape of the particles can be controlled by the method and can be spherical, pseudo-spherical, cylindrical, gyroid-shaped, rod-shaped, fiber-shaped, core-shell shaped particles, or mixtures thereof. Silica particles may be substantially spherical or pseudo-spherical.

The silica can be any silica. Silica may be biodegradable and/or soluble. Examples of silica are amorphous silica or synthetic amorphous silica.

Provided particles may have an MMAD of 0.5 to 15 μm. For delivery of bioactive compounds in the cardiopulmonary system, the particles may have an MMAD of 0.5 to 5 μm, or 0.5 to 3.5, or 0.6 to 4, or 0.75 to 3.5, or 1 to 3 μm, and a GSD of 2.5, or 2.2. , or 2.0, or 1.8, or 1.5, or less than 1.2, and the FPF may be at least 99.5%.

For delivery of bioactive compounds to the upper lung, nose, sublingual or postlingual, the particles are at least 5 μm, or 0.1 to 15 μm, or 5 to 12 μm, or 6.5 to 8.5, or 7.5 to 9.5, or 8.5 to 10.5, or It may have an MMAD of 9.5 to 11.5 μm, a GSD of less than 2.5, or 2.2, or 2.0, or 1.8, or 1.5, or 1.2, and an FPF of at least 99.0%.

Regardless of the site of delivery, the GSD of the particles may be 0.75 to 4, or 1 to 2.5, or 1 to 2, or 1 to 1.5.

The mass density may be less than 0.4, or 0.15 to 0.35 g/cm3.

The fine particle fraction (FPF) may be at least 60%, 75%, 80%, 85%, 90%, 95% or 99%. The FPF may be 95 to 99%, or 98 to 100%, or 99.5 to 100%, or 99.8 to 100%.

The particles obtained in the process of the invention can be used in pharmaceutical compositions adapted for pulmonary, nasal, sublingual and/or pharyngeal delivery of bioactive compounds.

The pharmaceutical composition may comprise a plurality of porous silica particles loaded at 0.01 to 85%, or 0.05 to 80%, or 0.1 to 70%, or 10 to 60%, or 25 to 58%, or This may consist of, where the percentage is a percentage of the total weight of the loaded particles. As mentioned above, more than one bioactive compound can be loaded in the particle. Alternatively, one or more bioactive compounds may be loaded within the particle or on and within the surface of the particle.

The concentration of porous silica particles in the pharmaceutical composition is 5% w/w or more, or 15%, 20%, 25%, 30%, 40%, 50%, 75%, 85%, 90%, based on the total weight of the pharmaceutical composition. It may be % w/w.

For diagnostic purposes, it may be advantageous to use particles, where the signaling or imaging compound is attached to or present on the outer surface of the particle. The imaging compound may be a labeling agent or tracer suitable for imaging, such as gamma scintigraphy, single proton emission computed tomography or positron emission tomography (PET), magnetic resonance imaging (MRI), or fluorescence imaging.

The pharmaceutical composition can be used in an inhalation device. The invention is not limited to any particular inhalation device, which may be a metered dose inhaler (MDI), dry powder inhaler (DPI) or mist inhaler (SMI). The pharmaceutical composition can be mixed with a propellant inside the inhalation device. The propellant may be selected from the group comprising: hydrocarbons, fluorocarbons, hydrogen-containing fluorocarbons, or mixtures thereof having a vapor pressure sufficient to efficiently form an aerosol upon activation of a metered dose inhaler. The pharmaceutical composition may have no or substantially no propellant.

The composition may further comprise or consist of other pharmaceutical excipients, diluents or additives. For example, surfactants, wetting agents, bulking agents, adhesion modifiers such as sugars, lipids, amino acids, surfactants, polymers and absorption enhancers can be used. Suitable pharmaceutical excipients (also referred to as carriers, diluents and excipients) can be found in "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988. Examples of excipients can be microcrystalline cellulose such as PH-101, hydroxypropyl cellulose such as low-substitution, saccharides such as mannitol, stearates such as magnesium stearate and cyclodextrins. The pharmaceutical composition may be free or substantially free of additives.

Pharmaceutical compositions for pulmonary delivery of bioactive compounds, optionally surface modified with functionalizing agents, have one or more bioactive compounds, and optionally other pharmaceutical excipients, diluents or additives, and comprise from 0.1 to 80% of the total weight of the loaded particles, or a plurality of porous silica particles loaded from 5 to 50%, wherein the particles have an MMAD of 0.5 to 5 μm, a GSD of less than 2.5, and an FPF of at least 99.5%. The particles may have an MMAD of 0.5 to 3.5 μm, a GSD of less than 1.5, and an FPF of at least 99.8%.

Pharmaceutical compositions for sublingual, nasal and/or pharyngeal delivery of a bioactive compound, optionally surface modified with a functionalizing agent, having one or more bioactive compounds, and optionally other pharmaceutical excipients, diluents or additives, and comprising the total weight of the loaded particles. and a plurality of porous silica particles loaded with 0.1 to 80%, or 5 to 50%, wherein the particles have an MMAD of 5 to 15 μm, a GSD of less than 2.5, and an FPF of at least 99.5%. The particles have an MMAD of 8 to 12 μm, a GSD of less than 2, and an FPF of at least 99.8%.

Pharmaceutical compositions for sublingual delivery of bioactive compounds may comprise or consist of a plurality of porous silica particles having one or more bioactive compounds and loaded from 0.1 to 85%, or from 5 to 50% of the total weight of the loaded particles. wherein the silica particles have an MMAD of at least 5 μm, a GSD of less than 2.5, an FPF of at least 99.5%, and the additives are low-substituted, saccharides such as mannitol, stearates such as magnesium stearate and cyclodextrins. is selected.

The total amount of bioactive compound in the dosage form may be 1 to 100 mg, or 1 to 50 mg, or 5 to 50 mg, or 5 to 25 mg.

The dosage form may be administered once or twice daily, as needed.

Bioactive compounds may be crystalline, amorphous or oily. Bioactive compounds can exist in both crystalline and amorphous forms depending on the solvent, salt, etc. One or more bioactive compounds have a water solubility at 25°C of Ph.Eur 9 ^th Ed. 10 mg/ml or more, or water solubility at 25℃ according to Ph.Eur 9 ^th Ed. 1 to 10 mg/ml, or water solubility at 25°C according to Ph.Eur 9 ^th Ed. Depending on the condition, it may be less than 1 mg/ml. If more than one bioactive compound is used, the water solubility may be different or the same.

The pharmaceutical composition can be used in the diagnosis of lung disease. The compositions may also be used for local and/or systemic diagnosis, prevention and/or treatment of disorders. The disorder may be a lung, nose, or pharyngeal disorder. Any pulmonary disorder is encompassed by this application. The disorder (or disease or condition) may be selected from the group including or consisting of infections, inflammation, COPD, asthma, cancer, tuberculosis, severe acute respiratory syndrome, respiratory syncytial virus, influenza, smallpox, and drug-resistant respiratory infections and systemic infections. You can.

Bioactive compounds include antiallergic agents, bronchodilators, pulmonary surfactants, analgesics, antibiotics, anti-infectives, leukotriene inhibitors or antagonists, antihistamines, anti-inflammatory agents, antineoplastic agents, anticancer agents, anticholinergics, anesthetics, antituberculous agents, cardiovascular agents, enzymes. , steroids, genetic material, viral vectors, antisense agents, proteins, peptides, and any combination thereof. Bioactive compounds include p2-adrenergic drugs, agonists, corticosteroids, non-steroidal drugs, anti-inflammatory drugs, antibiotics, anticholinergics, antivirals, mucolytics, prostacyclins, beta-blockers, anti-infectives, and smoking cessation drugs. cessation), angiotensin II receptor antagonist, anesthetic peptide, and any combination thereof.

Examples of bioactive compounds include formoterol, formoterol fumarate inhalation solution,

r-formoterol inhalation solution, salbutamol, salbutamol inhalation solution, (r-salbutamol) inhalation solution, pirbuterol, metaproterenol sulfate, clenbuterol, metaproterenol, terbu Talin, salmeterol, pirbuterol, procaterol, leproterol, bitolterol, fenoterol, tulobuterol, atenolol,

Salmeterol (r-salbutamol) Beclomethasone, Ciclesonide, Budesonide, Budesonide Inhalation Suspension, Fluticasone, Fluticasone Inhalation Suspension, Punisolide, Fluocotine Butyl, Beclomethasone Dipropio Nate, triamcinolone acetonide;

Beclomethasone/formoterol, fluticasone/salmeterol, ipratropium bromide/salbutamol, fenoterol/ipratropium bromide,

Cromolyn sodium, tobramycin inhalation solution, colistin inhalation solution, aztreonam inhalation solution, mometasone, tobramycin, pranlukast, nedocromil, amlexanox

Tiotropium bromide, ipratropium bromide, enalaprilat, enalapril,

Zanamivir, ribavirin, ipratropium bromide, terbutaline,

Recombinant human DNase, hypertonic saline inhalation solution, sodium cromoglycate or N-acetyl cysteine, or any mixture thereof,

It may be roloprost, metoprolol, propranolol, pentamidine, nicotine, losartan, sevoflurane, desflurane, enflurane, halothane, isoflurane, or any mixture thereof.

Examples of bioactive compounds are listed in Table 1 below.

The bioactive compound is selected from the group comprising or consisting of: gefitinib, dasatinib, imatinib, bosutinib, diclofenac (sodium), felodipine, indapamide, itraconazole, and quetiapine. Bioactive compounds may be clofazimine (NC009), OSU-03021 (NC023) and folic acid (NC026).

Experiment

particle manufacturing

A typical synthesis of nanoporous silica may be as follows: Pluronic 123 (triblock copolymer, EO20PO70EO20, Sigma-Aldrich) (4 g) as a templating agent and 1 as a swelling agent, with stirring at room temperature (RT) for 3 days. 3,5-Trimethylbenzene (TMB) (mesitylene, Sigma-Aldrich) (3.3 g) was dissolved in 127 ml distilled H ₂ O and 20 ml hydrochloric acid (HCl, 37%, Sigma-Aldrich). The solution was preheated to 40° C. and then 9.14 ml TEOS (tetraethyl orthosilicate, Sigma-Aldrich) was added. The mixture was stirred at a speed of 500 rpm for a further 10 min and then held at 40°C for 24 hours before being hydrothermally treated in an oven at 100°C for a further 24 hours. Finally, the mixture was filtered, washed and dried at room temperature. The product was calcined to remove the surfactant template and swelling agent. Firing was carried out by heating to 600°C at a heating rate of 1.5°C/min, holding at 600°C for 6 hours, and then cooling to ambient conditions. The product obtained is a white powder composed of porous silica particles.

Example of particle separation

100 g of raw nanoporous silica was fed into the air classifier, the air flow was adjusted from 53 to 42 m3/h, the speed was adjusted from 2475 to 13500 rpm, and 11 g of fines (size about 10% of GSD) were fed into the air classifier. 8 g of coarse material (particles with a size greater than approximately 90% of the GSD) were collected. The particle size distribution D ₉₀ /D ₁₀ was narrowed from 4.5 to 1.8.

As shown in Figure 2, the GSD narrowed from 2.28 to 1.8 after air classifier, meaning that the geometric standard deviation (GSD) can be adjusted using the air classifier. Figure 4 shows that the GSD of silica particles loaded with bioactive compounds becomes narrower than the GSD of unloaded or naked silica particles.

Example of drug loading

2 g of nanoporous silica was added to 2 g of NLAB compound NC026 and 100 ml of concentrated methanol solution. The mixture was heated to 40° C. and stirred for 30 min. Methanol was evaporated under vacuum. The loading concentration by mass was 50%.

The two bioactive compounds were also loaded sequentially onto the same particles. Bioactive compounds NC009 and NC023 were successfully loaded into silica particles. Figure 3 shows thermogravimetric analysis (TGA) results, showing that both bioactive compounds were loaded into the porous silica particles.

Example 1:

100 mg NLAB-silica particles were added to 500 ml simulated lung fluid (SLF) and shaken at 37°C at a shaking speed of 100 rpm. Samples were taken at some time points and filtered. The concentration of Si was measured by inductively coupled plasma-atomic emission spectroscopy (ICP-AES).

By comparing the samples in FIG. 7 with different particle sizes but similar pore structures, it was confirmed how particle size affects silica dissolution. It was shown that 12 μm and 3 μm particles have similar porosity and the same dissolution kinetics.

Example 2:

50 mg NLAB-silica particles were added to 500 ml simulated lung fluid (SLF) and shaken at 37°C at a shaking speed of 100 rpm. Samples were taken at some time points and filtered. The concentration of Si was measured by inductively coupled plasma-atomic emission spectroscopy (ICP-AES).

Figure 2 showed that different pore structures were the main parameter for the dissolution rate of silica in SLF. Silicon hydroxyl groups slightly changed the dissolution rate of silica in SLF. 95% of silica can be completely dissolved within 24 hours.

Example 3:

5-20 mg loaded or unloaded particles were charged into one monodose inhaler, followed by suction in a simulated inhalation device. The capsule mass was weighed before and after suction to test the residual amount of particles attached to the capsule. As shown in Table 2, particles coated with amino acids dramatically reduced the amount of particles remaining in the capsule.

Table 2.

The invention is not limited to the disclosed aspects, but may be modified and modified within the scope of the following claims.

Claims (38)

A method for preparing loaded porous silica particles comprising one or more bioactive compounds, comprising the following steps:
a) providing silica particles, wherein the silica particles have a molecular weight of 1 to 100 nm, calculated using the BET (Brunauer-Emmett-Teller) model to calculate pore volume and pore size, and determined by nitrogen adsorption isotherm. with a pore size of 0.1 to 3 cm3/g and a surface area of 40 to 1200 m2/g,
b) Particles with a mass median aerodynamic diameter (MMAD) of 0.5 to 15 ㎛ and a geometric standard deviation (D _84.1 /D _15.9 ) ^1/2 (GSD) of less than 2.5 separating the particles to obtain, and
c) loading the obtained particles with one or more bioactive compounds, wherein the bioactive compounds are crystalline, or amorphous or oily compounds. 2. The method of claim 1, further comprising the step of d) loading the particles with an additional bioactive compound. The method of claim 1, wherein the particles have an MMAD of 0.5 to 3.5 μm and a GSD of less than 1.5. The method of claim 1, wherein the particles have an MMAD of 8 to 12 μm and a GSD of less than 2. The method of claim 1, wherein the particles have a fine particle fraction (FPF) of 95 to 99%. 2. The method of claim 1, wherein the method comprises an additional step of surface modification of the particles prior to separation or prior to loading. delete delete delete 7. The method according to any one of claims 1 to 6, wherein after stirring or spraying the solution, droplets are formed by gelation of the silica through a change in pH and/or evaporation of the aqueous phase. A method for producing loaded porous silica particles, wherein the silica particles are produced by a sol-gel process involving a condensation reaction of a chemical organic solution, oil, or liquid polymer. 7. The method according to any one of claims 1 to 6, wherein the silica particles are pseudo-spherical or cylindrical. 7. The method of any one of claims 1 to 6, wherein the silica particles have a pore volume and pore size of 2 to A method for producing loaded porous silica particles with a pore size of 50 nm, a pore volume of 0.5 to 1.5 cm 3 /g and a surface area of 50 to 800 m 2 /g. delete delete delete delete delete delete delete A pharmaceutical composition adapted for pulmonary delivery of a bioactive compound, comprising a plurality of porous silica particles loaded with one or more bioactive compounds, from 0.1 to 80% of the total weight of the loaded particles, wherein the particles are 0.5 to 5 μm. _The silica particles have ^a mass median aerodynamic diameter (MMAD ₎ of -Teller) model and has a pore size of 1 to 100 nm, a pore volume of 0.1 to 3 cm3/g and a surface area of 40 to 1200 m2/g, as measured by the nitrogen adsorption isotherm, and the bioactive compound A pharmaceutical composition characterized in that it is a crystalline, amorphous, or oily compound. 21. The pharmaceutical composition according to claim 20, wherein the particles have an MMAD of 0.5 to 3.5 μm and a GSD of less than 1.5. 1. A pharmaceutical composition adapted for sublingual, nasal and/or pharyngeal delivery of a bioactive compound, comprising a plurality of porous silica particles loaded with one or more bioactive compounds from 0.1 to 80% of the total weight of the loaded particles, comprising: The particles have a mass median aerodynamic diameter (MMAD) of 5 to 15 μm, the geometric standard deviation (D _84.1 /D _15.9 ) ^1/2 (GSD) is less than 2.5, and the silica particles have a pore volume and pore size. A pore size of 1 to 100 nm, a pore volume of 0.1 to 3 cm/g and a surface area of 40 to 1200 m2/g were calculated using the BET (Brunauer-Emmett-Teller) model and measured by nitrogen adsorption isotherms. A pharmaceutical composition, wherein the bioactive compound is a crystalline, amorphous, or oily compound. 23. The pharmaceutical composition according to claim 22, wherein the particles have an MMAD of 8 to 12 μm and a GSD of less than 2. 24. The pharmaceutical composition according to any one of claims 20 to 23, wherein the particles have a fine particle fraction (FPF) of 95 to 99%. 24. The pharmaceutical composition according to any one of claims 20 to 23, wherein the particles are prepared according to the process according to claim 1. delete delete delete delete 24. The method according to any one of claims 20 to 23, selected from the group comprising infection, inflammation, COPD, asthma, cancer, tuberculosis, severe acute respiratory syndrome, respiratory syncytial virus, influenza, smallpox and drug-resistant respiratory infections. Pharmaceutical compositions for diagnostic, prophylactic and/or therapeutic use in disorders of the lung, nose, sublingual or pharynx. 7. The method according to any one of claims 1 to 6, wherein the bioactive compound is an anti-allergic agent, bronchodilator, pulmonary lung surfactant, analgesic agent, antibiotic, anti-infective agent, leukotriene inhibitor or antagonist, antihistamine, Loaded porous silica particles selected from the group comprising anti-inflammatory agents, antineoplastic agents, anticancer agents, anticholinergics, anesthetics, antitubercular agents, cardiovascular agents, enzymes, steroids, genetic material, viral vectors, antisense agents, proteins, peptides, and combinations thereof. Manufacturing method. 7. The method according to any one of claims 1 to 6, wherein the bioactive compound is selected from the group consisting of gefitinib, dasatinib, imatinib, bosutinib, diclofenac (sodium), felodipine, indapamide, itraconazole, quetiapine, clofenac A method for producing loaded porous silica particles selected from the group comprising phagemin (NC009), OSU-03021 (NC023) and folic acid (NC026). delete delete 1. An inhalation device filled with a dry powder pharmaceutical composition for pulmonary, nasal, sublingual and/or pharyngeal administration, comprising a plurality of porous particles loaded with one or more bioactive compounds, comprising:
An inhalation device wherein the particles are produced by a method comprising the following steps:
a) providing porous particles, or preparing them by a sol-gel method or a spray drying method,
wherein the particles have a pore size of 1 to 100 nm, a pore volume of 0.1 to 3 cm3/g and a surface area of 40 to 1200 m2/g,
Particles are pseudo-spherical or cylindrical;
b) separating the particles before loading, or using an air classifier, or cyclonic separation, or clarification, or sedimentation and/or sieving,
particles having a mass median aerodynamic diameter (MMAD) of 0.5 to 15 μm, a geometric standard deviation (D _84.1 /D _15.9 ) ^1/2 (GSD) of less than 2.5, and a fine particle fraction (FPF) of at least 99.0%. steps to obtain,
c) loading the particles with one or more bioactive compounds, or loading the particles with one or more bioactive compounds by solvent evaporation, impregnation, spray-drying, melting, supercritical CO ₂ loading or freeze-drying, The compound is a crystalline, amorphous or oily compound,
wherein the porous silica particles are loaded with at least 5% w/w of one or more bioactive compounds. 36. The inhalation device of claim 35, wherein the method further comprises d) modifying the surface of the particle, or modifying the surface of the particle by etching and/or coating or a coating that does not clog the pores. 37. The method of claim 35 or 36, wherein the method comprises the step e) loading the particles with an additional bioactive compound, wherein the concentration of porous silica particles in the dry powder pharmaceutical composition is based on the total weight of the dry powder pharmaceutical composition. An inhalation device further comprising a step of at least 5% w/w. 36. The inhalation device of claim 35, wherein the dry powder pharmaceutical composition is mixed with propellants and other pharmaceutical excipients, diluents or additives.